Vascular Endothelial Growth Factor–Regulated Gene Expression in Endothelial Cells

Liú, Dan; Jia, Hao; Holmes, David; Stannard, Anita K.; Zachary, Ian

doi:10.1161/01.atv.0000098644.03153.6f

Cited by 152 publications

(100 citation statements)

References 41 publications

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“…VEGF is a pivotal mediator of this process, but while the array of endothelial genes upregulated by VEGF has been described (Abe and Sato, 2001;Liu et al, 2003), the role of individual gene functions regulated by VEGF is poorly understood. A previous study reported that inhibition of Egr1 protein expression by DNAzymes blocked serum-induced proliferation and migration and perturbed pre-existing tubular structures in Matrigel (Fahmy et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous findings demonstrated that FGF-2 also significantly upregulated Egr3 expression, but caused a much smaller increase in expression of the NR4A gene family (Liu et al, 2003). The induction of Egr3 by FGF-2, although weaker than that of VEGF ( Figure 3a), prompted us to also examine the effects of Egr3 siRNA on the biological response to FGF-2.…”

Section: Vegf Regulation Of Egr3 D Liu Et Almentioning

confidence: 90%

“…Time-course experiments revealed that VEGF-mediated Egr activation reached a peak at 45 min, which was maintained for 90 min and gradually diminished after 3 h, returning to the basal level after 5 h ( Figure 1c). We previously reported that VEGF-induced Egr3 mRNA expression was mediated via KDR, PKC and extracellular signal-regulated kinase (ERK) signalling pathways (Liu et al, 2003). In order to examine whether Egr transcriptional activation was mediated through the same signalling pathways, HUVECs were preincubated with SU5614, GF109203X and U0126, Figure 1 Vascular endothelial growth factor (VEGF) regulation of Early growth response (Egr) gene expression and transcriptional activation.…”

Section: Vegf Regulation Of Egr Transcription Factors and Egr Transcrmentioning

confidence: 99%

“…The induction of Egr3 by FGF-2, although weaker than that of VEGF ( Figure 3a), prompted us to also examine the effects of Egr3 siRNA on the biological response to FGF-2. In addition, we investigated the effects of siRNA-mediated knockdown of Nur77, the member of the NR4A nuclear receptor subfamily, most strongly induced by VEGF (Liu et al, 2003). Egr3 and Nur77 siRNAs markedly reduced both basal mRNA expression and mRNA expression induced by VEGF or FGF-2 (Figures 3a and b).…”

Section: Vegf Regulation Of Egr3 D Liu Et Almentioning

confidence: 99%

“…KDR is activated through ligandstimulated receptor dimerization and trans(auto)phosphorylation of multiple tyrosine residues in the cytoplasmic domain (Dougher and Terman, 1999;Takahashi et al, 2001), triggering an array of early signalling events mediating cellular biological responses, including production of prostacyclin and nitric oxide, increased cell survival, migration, proliferation and angiogenesis (Waltenberger et al, 1994;Xia et al, 1996;Abedi and Zachary, 1997;Laitinen et al, 1997;Wheeler-Jones et al, 1997;Gerber et al, 1998;AbuGhazaleh et al, 2001;Gliki et al, 2001;Takahashi et al, 2001;Zachary, 2003). The role of gene expression in endothelial functions regulated by VEGF-A 165 is still poorly understood, but recent findings from cDNA and oligonucleotide array screening have identified the endothelial gene expression profile induced by VEGF-A 165 (Abe and Sato, 2001;Liu et al, 2003). We identified four immediate-early genes that were most strongly upregulated by VEGF, early growth response 3 (Egr3), and the NR4A1 family of nuclear receptors (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor1).…”

Section: Introductionmentioning

confidence: 99%

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The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Section: Vegf Regulation Of Egr3 D Liu Et Almentioning

confidence: 90%

Section: Vegf Regulation Of Egr Transcription Factors and Egr Transcrmentioning

confidence: 99%

Section: Vegf Regulation Of Egr3 D Liu Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis

et al. 2007

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Haplotypes of theNR4A2/NURR1gene and cardiovascular disease: The Rotterdam Study

et al. 2009

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Nuclear receptor subfamily 4, group A, member 2 (NR4A2, also called Nurr1) has lately become of interest with regard to atherogenesis. We examined the association between common variation in the NR4A2 gene and cardiovascular disease in the Rotterdam Study, a prospective population-based study among persons aged > or = 55 years. Three SNPs that tag common haplotypes across a 36-kb region surrounding the NR4A2 gene were determined. Four haplotypes with frequencies >1% covered 96% of the genetic variation. In 5,650 participants without history of coronary heart disease, 729 coronary heart disease events occurred during a median follow-up time of 11.9 years. NR4A2 haplotypes were neither associated with coronary events nor with intima-media thickness (IMT), carotid plaques, or ankle-arm index (AAI). NR4A2 haplotypes showed a tendency toward associations with aortic and coronary calcification (haplo.score global simulation P values 0.076 and 0.075, respectively), which seemed to be based on haplotype 2 (individual P values were both P=0.015). Furthermore, NR4A2 haplotype 3 was associated with higher high-density lipoprotein (HDL) cholesterol and haplotype 4 with lower systolic blood pressure. In conclusion, NR4A2/NURR1 haplotypes were not associated with coronary events, carotid IMT, carotid plaques, or AAI. There was a tendency toward associations with aortic calcification and coronary calcification. Associations for NR4A2 were found with both HDL levels and blood pressure. It remains to be investigated which pathophysiological mechanisms pertain to NR4A2 function in cardiovascular disease.

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VEGF stimulates PKD‐mediated CREB‐dependent orphan nuclear receptor Nurr1 expression: Role in VEGF‐induced angiogenesis

Zhao

Desai

Zeng

2010

Intl Journal of Cancer

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New vessel formation is critical for solid tumor growth and it is primarily stimulated by the most potent angiogenic factor vascular endothelial growth factor (VEGF or VEGF-A165). VEGF promotes endothelial cell proliferation by initiating signaling cascades to increase gene transcription. Recent works showed that VEGF potently and rapidly induces expression of orphan nuclear receptor Nurr1 in endothelial cells. However, the signaling pathway for VEGF-induced Nurr1 expression and its role in VEGF-induced endothelial cell proliferation and angiogenic response have not been examined. In our study, we first show that VEGF significantly induces expression of Nurr1 mRNA, protein and its promoter activity in cultured endothelial cells. Furthermore, the promoter analysis shows that deletion of the putative cAMP-responsive element binding protein (CREB) site in the proximal region of the promoter markedly reduces VEGF-induced promoter activity whereas deletion of the upstream NF-jB site has moderate effect. Transfection of a dominant negative CREB mutant (K-CREB) or mutation of this putative CREB site in the Nurr1 promoter attenuates VEGF-induced Nurr1 expression. VEGF also stimulates the binding of nuclear CREB protein to its site in the Nurr1 promoter in vitro and in vivo. Moreover, using pharmacological inhibitors and molecular approaches, we show that VEGF-induced CREB activation is largely mediated by protein kinase C-dependent protein kinase D activation. Finally, our data indicate that knockdown of endogenous Nurr1 expression attenuates VEGF-induced endothelial cell proliferation, migration and in vivo matrigel angiogenesis, suggesting its potential importance in mediating VEGF-induced tumor angiogenesis.

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Vascular Endothelial Growth Factor–Regulated Gene Expression in Endothelial Cells

Cited by 152 publications

References 41 publications

The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis

The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis

Haplotypes of theNR4A2/NURR1gene and cardiovascular disease: The Rotterdam Study

VEGF stimulates PKD‐mediated CREB‐dependent orphan nuclear receptor Nurr1 expression: Role in VEGF‐induced angiogenesis

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